CN106220741A - Fgf‑23的重组长效拮抗肽及其制备和应用 - Google Patents
Fgf‑23的重组长效拮抗肽及其制备和应用 Download PDFInfo
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- CN106220741A CN106220741A CN201610720198.XA CN201610720198A CN106220741A CN 106220741 A CN106220741 A CN 106220741A CN 201610720198 A CN201610720198 A CN 201610720198A CN 106220741 A CN106220741 A CN 106220741A
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Abstract
本发明提供了新的成纤维细胞生长因子‑23（FGF‑23）拮抗肽的融合蛋白，包括FGF‑23改构体肽和载体蛋白。其中，所述FGF‑23改构体肽具有拮抗FGF‑23的生物学活性，而且所述载体蛋白具有延长体内半衰期的作用。所述融合蛋白的药物半衰期大幅提高，可用于预防和治疗矿物质的代谢失衡及由其引发的疾病，如低磷血症和慢性肾病等。
Description
技术领域
本发明属于多肽和蛋白质技术领域，具体而言，本发明涉及融合蛋白，其包括FGF-23的拮抗肽和载体蛋白。另外，本发明还涉及该融合蛋白的表达及制备方法和应用等。
背景技术
成纤维细胞生长因子（FGF）家族是人体中存在最大的生长因子家族之一，包括18个成员。FGF信号传递在人类生命循环中扮演着极为重要和独特的角色：在胚胎阶段，FGF信号传导是上皮-介质交流（mesenchymal-epithelial communication）的主要调控者，因此部分决定着器官形成；在成人中，FGF信号传导除继续调控组织内稳态外，在伤口愈合，组织修复，胆固醇／胆汁酸代谢和糖脂代谢也扮演着重要的角色。而且随着对FGFs研究的深入，人们还发现FGFs家族新成员FGF23在血磷调控中发挥着极其重要的作用。
磷元素是人体遗传物质核酸的重要组分，也是人类能量转换的关键物质三磷酸腺苷(ATP)的重要成分，磷还是多种酶和生物膜磷脂的组分，是构成骨骼、牙齿的重要元素；磷元素在细胞结构、能量代谢、信号传导、离子转运等基本生理过程中都发挥着极其重要的作用。血液中正常的磷浓度范围为2.2-4.9 mg/dL，主要由肾小管的重吸收调控。由于磷元素的多效性，所以磷元素动态平衡的失衡造成的副作用将影响到每一个重要的组织/器官。低磷血症是磷代谢失常的一种体现形式，相比于高磷血症，在临床上更为常见，除由于主观原因引起磷吸入减少或者慢性肾脏病（chronic kidney disease, CKD）引起磷代谢紊乱外，诸如呼吸衰竭、心功能不全、甲状腺功能亢进、糖尿病酮症酸中毒以及外科手术等也会引起不同程度的低磷血症。低磷可引起细胞能量代谢的广泛紊乱，造成细胞内能量危机，从而严重影响神经传导、骨骼发育、肌肉收缩和心肌功能，加重病人病情甚至危及生命。X连锁低磷酸盐血症（X-Linked Hypophosphatemia，XLH）、常染色体显性遗传性低磷血症性佝偻病（autosomal dominant hypophosphatemic rickets，ADHR）、常染色体隐性低血磷性佝偻病(autosomal recessive hypophosphatemicrickets，ARHR)以及肿瘤性骨软化病（tumor-induced osteomalacia，TIO）均属于典型的低磷血症（表现形式）。随着临床低磷血症发病率的上升以及人们对低磷血症危害认识的提高，有关低磷血症发病机制以及相应治疗药物研究日益受到科研工作者和临床医生的广泛关注。
口腔或静脉注射无机磷盐目前是治疗低血磷症的主要方式，但口服磷酸盐需要的剂量高，这经常会导致腹泻或对胃的刺激。而静脉注射磷酸盐，对于给定的药物的准确剂量通常是不可预知的且不可控制，包括“突发性”高血磷、低血钙和转移性钙化等。以遗传性磷酸盐代谢紊乱中最常见的一类疾病X连锁低磷酸盐血症（XLH）为例，XLH患者具有长时间的甚至非常严重的肾磷酸盐消耗，大部分的治疗方案能够引起肾钙化和肾结石。目前国际上针对XLH仅存的另一种疗法，是使用生长激素提高患有XLH儿童的身高，但这使得患者会提前出现骨骼畸形。另外，对于那些由肿瘤引起的骨软化症而导致的肾磷酸盐消耗过量的患者，一个理论层面合理的治疗方案就是切除这种产生过量的调磷荷尔蒙因子的肿瘤，然而，这些肿瘤往往是很难定位的，即使肿瘤被位定位也是很难到达，因此大部分肿瘤引起的骨软化症患者，目前尚无行之有效的治疗方案。
近几年，临床研究发现所有上述磷代谢紊乱都有一个共同的特征，即血清中含有较高水平的成纤维细胞生长因子23（FGF23）。FGF23是成纤维细胞生长因子家族（FGFs）的成员，是一种重要的内分泌磷稳态调节因子。FGF23基因位于染色体12p12区，编码251个氨基酸的蛋白，血清中FGF23主要由成骨细胞分泌，肾脏是FGF23主要的靶器官。健康成人尿中可以检测到FGF23，提示肾脏可能是FGF23清除的主要器官。研究表明，FGF23通过近曲小管上皮细胞刷状缘膜上的钠-磷协同转运蛋白NPT2a和NPT2c的内移和降解增加尿磷的排泄，减少肾脏无机磷重吸收从而调节磷的排泄。此外，通过抑制肾脏1a-羟化酶活性，FGF23可降低体内活性维生素D[1,25(OH)2D3]水平，进一步加重甲状旁腺功能亢进，导致一系列骨组织学改变和心血管疾病的发生。
大量的研究也证实肾近曲小管中过高的FGF23是导致磷酸盐代谢紊乱和相关后遗症的关键原因。事实上，当前口服磷酸盐疗法反而会在一定程度上导致血清中FGF23的进一步升高，从而形成了恶性循环。
本发明人的中国专利ZL 201310159797.5开发了一种FGF23的拮抗肽及其的聚乙二醇或葡聚糖的缀合物，用于预防或治疗低磷血症。然而，近年来的临床试验中多有发现聚乙二醇等非天然物质容易引起人体的免疫反应，导致无法成药。
本发明人没有如同一般技术人员那般放弃，而是继续经过艰苦努力开发了新的FGF23的拮抗肽（其与FGF23本身具有一定的氨基酸序列的同一性，故而在本文中被称为FGF-23 改构体肽，简称为FGF*），然而其虽然给药后短期内能降低尿磷水平并提高血磷水平，但是给药后时间长了调磷效果不明显，甚至尿磷出现了上升。本发明人没有继续如同一般技术人员那般放弃，而是再接再厉地经过艰苦努力开发了新的FGF23改构体肽的融合蛋白，给药后长期调磷效果显著，更令人意外的是，通常融合蛋白需要连接肽连接并且生物活性部分位于蛋白折叠起始的N端，然而，本发明的FGF23改构体肽无需如此。
发明内容
本发明要解决的技术问题是提供新的FGF-23拮抗肽或其融合蛋白。另外，本发明还提供了它们的制备方法和中间产物（如，基因、表达系统等）以及应用等。
具体而言，在第一方面，本发明提供了融合蛋白，其包括FGF-23 改构体肽和载体蛋白，其中，所述FGF-23 改构体肽具有拮抗FGF-23的生物学活性，而且所述载体蛋白具有延长体内半衰期的作用。
优选在本发明第一方面的融合蛋白中，所述FGF-23 改构体肽竞争结合受体FGFR1和共受体a-klotho而拮抗FGF-23。在本发明的具体实施方式中，所述FGF-23 改构体的氨基酸序列如SEQ ID NO：1、2或3所示。
优选在本发明第一方面的融合蛋白中，所述载体蛋白是血清白蛋白，更优选是人血清白蛋白（HSA）。在本发明的具体实施方式中，所述HSA的氨基酸序列如SEQ ID NO：4所示。
也优选在本发明第一方面的融合蛋白中，所述载体蛋白是抗体片段，更优选是Fc，更加优选是人IgG Fc。所述人IgG Fc可以是人IgG1、IgG2、IgG3或IgG4的Fc。在本发明的具体实施方式中，所述人IgG Fc的氨基酸序列如SEQ ID NO：5所示。
优选本发明第一方面的融合蛋白由FGF-23 改构体肽和载体蛋白组成，即其中不包括连接肽，而使得FGF-23 改构体肽和载体蛋白直接连接。这种方式在融合蛋白构建中不常用，但是本发明人发现对于本发明的FGF-23 改构体肽来说可行。
也优选本发明第一方面的融合蛋白由FGF-23 改构体肽、连接肽和载体蛋白组成，即其中包括连接肽，位于FGF-23 改构体肽和载体蛋白之间。优选所述连接肽的氨基酸序列如(GGGGS)n所示，其中n为1、2、3、4、5或6。
优选在本发明第一方面的融合蛋白中，所述FGF-23 改构体肽位于所述融合蛋白的N端，而且所述载体蛋白位于所述融合蛋白的C端。
也优选在本发明第一方面的融合蛋白中，所述FGF-23 改构体肽位于所述融合蛋白的C端，而且所述载体蛋白位于所述融合蛋白的N端。由于决定蛋白质活性的折叠通常从N端起始，因此这种方式在融合蛋白构建中不常用，但是本发明人发现对于本发明的FGF-23改构体肽来说可行。
在第二方面，本发明提供了编码本发明第一方面的融合蛋白的多核苷酸（基因）。根据氨基酸和密码子的对应关系，本领域技术人员能够根据权利要求1-6之一的融合蛋白获得编码其的基因。
在第三方面，本发明提供了包含本发明第二方面的多核苷酸的表达系统。在本文中，表达系统指的是能够表达相应多核苷酸的细胞或非细胞载体。细胞包括原核细胞和真核细胞。优选所述表达系统是酵母表达系统、昆虫表达系统或哺乳动物细胞（优选是CHO）表达系统。其中哺乳动物细胞表达系统可以利用高效表达质粒pMH3构建（参见国际专利WO2008091276A）
在第四方面，本发明提供了制备本发明第一方面的融合蛋白的方法，其包括在适宜的条件下使用权利要求8所述的表达系统表达本发明第一方面的融合蛋白，然后纯化。
在第五方面，本发明提供了本发明第一方面的融合蛋白在制备用于预防或治疗FGF-23表达升高而导致的疾病的药物中的应用。优选所述疾病是矿物质代谢失衡或其引发的疾病，如低磷血症、慢性肾病和/或慢性心肌病。
在另一个方面，本发明提供了FGF-23 改构体及其编码基因、包含所述编码基因的表达载体和制备方法，其中所述FGF-23 改构体的氨基酸序列如SEQ ID NO：1、2或3所示。
本发明取得的有益效果在于：本发明的融合蛋白适宜规模化表达，其体外稳定性显著提高、体内半衰期显著延长、体内免疫原性显著降低，能用于防治和治疗包括低磷血症等的疾病。
为了便于理解，本发明引用了公开文献，这些文献是为了更清楚地描述本发明，其全文内容均纳入本文进行参考。以下将通过具体的实施例和附图对本发明进行详细地描述。需要特别指出的是，这些描述仅仅是示例性的描述，并不构成对本发明范围的限制。依据本说明书的论述，本发明的许多变化、改变对所属领域技术人员来说都是显而易见了。
附图说明
图1 和图2显示了FGF-23改构体肽及其融合蛋白XLH小鼠的低磷血症的尿、血磷水平在不同时间的调节情况。
具体实施方式
本发明实施例所用的FGF-23 改构体肽为如 SEQ ID NO.2所示氨基酸序列的蛋白质，其中所用的试剂均为可通过公开渠道购买的化学纯的商品试剂。
实施例一 FGF23*-HSA的制备
委托温州医科大学构建表达FGF23*-HSA融合蛋白的酵母工程菌株并表达纯化，过程简而言之：通过融合PCR获得FGF23*-HSA的融合基因，融合基因5，和3，端分别设计EcoRⅠ和NotⅠ酶切位点。酶切后与pPIC9K载体连接，电转到毕赤酵母GS115感受态的菌株中，在3mg/mL的G418抗性中筛选，获得高产的转化阳性菌株，上罐发酵培养。培养液离心过滤分离后，上清液依次通过Blue sepharose柱、Phenyl Sepharose 疏水层析柱和Q Sepharose纯化，获得FGF23*-HSA。
FGF23*-HSA在50 L发酵罐的产量可以稳定维持在250 mg/L左右，最终的纯度高达95.3%（达到药用标准），总回收率在18~24%。
实施例二 FGF23*-GGGGS-HSA的制备
基本同实施例一，所不同的是融合基因的设计中增加了氨基酸序列为GGGGS的接头，委托制备FGF23*-GGGGS-HSA。
实施例三 FGF23*-(GGGGS)2-HSA的酵母工程菌株构建及制备
基本同实施例一，所不同的是融合基因的设计中增加了氨基酸序列为GGGGSGGGGS的接头，委托制备FGF23*-(GGGGS)2-HSA。
实施例四 HSA-FGF23*的制备
基本同实施例一，所不同的是融合基因的设计调换了次序，使得HSA位于FGF23*的N末端，委托制备HSA-FGF23*。
实施例五 HSA-GGGGS-FGF23*的制备
基本同实施例四，所不同的是融合基因的设计中增加了氨基酸序列为GGGGS的接头，委托制备HSA-GGGGS-FGF23*。
实施例六 HSA-(GGGGS)2-FGF23*的制备
基本同实施例四，所不同的是融合基因的设计中增加了氨基酸序列为GGGGSGGGGS的接头，委托制备HSA-(GGGGS)2-FGF23*。
实施例七 FGF23*-Fc的制备
基本同实施例一，所不同的是融合基因的设计中将HSA替换为Fc，委托制备FGF23*-Fc。
另外，委托温州医科大学构建表达FGF23*-HSA融合蛋白的哺乳动物表达系统并表达纯化，过程简而言之：通过融合PCR获得FGF23*-Fc的融合基因，融合基因5，和3，端分别设计EcoRⅠ和NotⅠ酶切位点。酶切后与pMH3载体连接，在鲑鱼精DNA的介导下，转染入CHO细胞，在1.2-1.8mg/mL的G418抗性中筛选，并通过1通过Dot blot和WB检测表达情况，获得高产的转化阳性细胞株，上罐发酵培养，第三天细胞密度即可高达8.78*106 cell/mL，最终的蛋白发酵量可达到487 mg/L。培养液离心过滤分离后，上清液依次通过protein A柱、Phenyl Sepharose 疏水层析柱和Q Sepharose纯化，获得FGF23*-Fc。
实施例八 FGF23*-GGGGS-Fc的制备
基本同实施例七，所不同的是融合基因的设计中增加了氨基酸序列为GGGGS的接头，委托制备FGF23*-GGGGS-Fc。
实施例九 FGF23*-(GGGGS)2-Fc的制备
基本同实施例七，所不同的是融合基因的设计中增加了氨基酸序列为GGGGSGGGGS的接头，委托制备FGF23*-(GGGGS)2-Fc。
实施例十 Fc-FGF23*的制备
基本同实施例七，所不同的是融合基因的设计调换了次序，使得Fc位于FGF23*的N末端，委托制备Fc-FGF23*。
同时，也基本如实施例7，委托构建哺乳动物表达系统，制备Fc-FGF23*。
实施例十一 Fc-GGGGS-FGF23*的制备
基本同实施例十，所不同的是融合基因的设计中增加了氨基酸序列为GGGGS的接头，委托制备Fc-GGGGS-FGF23*。
实施例十二 Fc-(GGGGS)2-FGF23*的制备
基本同实施例十，所不同的是融合基因的设计中增加了氨基酸序列为GGGGSGGGGS的接头，委托制备Fc-GGGGSGGGGS-FGF23*。
实施例十三 FGF23*对XLH小鼠血磷调节的作用
取X连锁佝偻病小鼠(X-linked hypophosphatemic rickets mice, XLH)的低磷血症鼠，雌雄随机分组，A组为模型组，注射生理盐水；B组注射FGF23*；C组注射等量FGF23*-HSA；D组注射等量FGF23*-Fc。注射给药前测定各小鼠尿液及血液含磷水平，给药4小时后测定各小鼠尿液和血液含磷水平，给药16小时后再测定各小鼠尿液及血液中含磷水平。结果如图1和图2所示，给药4小时后，FGF23*、FGF23*-HSA和FGF23*-Fc均能使尿液中含磷水平显著降低，并使血液中含磷水平显著提高，这说明FGF-23 改构体肽本身就能显著降低磷的代谢，提高体内含磷水平，从而有效抑制FGF-23引起的体内低磷症状；在给药时间达16小时后，FGF23*基本失效，甚至尿磷出现了上升，而修饰的FGF-23 FGF23*-HSA和FGF23*-Fc均较好地保留了上述调磷效应。另外，测试了其他连接次序和使用接头肽的情况，倒置也基本能保持上述效果，而使用接头肽也基本没有效果的替身；使用如 SEQ ID NO.1和3所示的FGF-23改构体肽，也显示了上述趋势，但是效果是SEQ ID NO.2最佳，SEQ ID NO.1次之。
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温州生长因子生物科技有限公司
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Claims (10)
1.融合蛋白，其包括FGF-23 改构体肽和载体蛋白，其中，所述FGF-23 改构体肽具有拮抗FGF-23的生物学活性，而且所述载体蛋白具有延长体内半衰期的作用。
2.权利要求1所述的融合蛋白，其中，所述FGF-23 改构体肽竞争结合受体FGFR1和共受体a-klotho而拮抗FGF-23，优选所述FGF-23 改构体的氨基酸序列如SEQ ID NO：1、2或3所示。
3.权利要求1所述的融合蛋白，其中，所述载体蛋白是血清白蛋白（优选是HSA，更优选所述HSA的氨基酸序列如SEQ ID NO：4所示）或抗体片段（优选是Fc，更优选是人IgG Fc）。
4.权利要求3所述的融合蛋白，其中所述人IgG Fc是人IgG1、IgG2、IgG3或IgG4的Fc，优选所述人IgG Fc的氨基酸序列如SEQ ID NO：5所示。
5.权利要求1所述的融合蛋白，其由FGF-23 改构体肽和载体蛋白组成，或者其由FGF-23 改构体肽、连接肽和载体蛋白组成，优选其中，所述连接肽的氨基酸序列如(GGGGS)n所示，其中n为1、2、3、4、5或6。
6.权利要求1所述的融合蛋白，其中，所述FGF-23 改构体肽位于所述融合蛋白的N端，而且所述载体蛋白位于所述融合蛋白的C端；或者，所述FGF-23 改构体肽位于所述融合蛋白的C端，而且所述载体蛋白位于所述融合蛋白的N端。
7.编码权利要求1-6之一的融合蛋白的多核苷酸。
8.包含权利要求7所述多核苷酸的表达系统，优选所述表达系统是酵母表达系统、昆虫表达系统或哺乳动物细胞（优选是CHO）表达系统。
9.制备权利要求1-6之一的融合蛋白的方法，其包括在适宜的条件下使用权利要求8所述的表达系统表达权利要求1-6之一的融合蛋白，然后纯化。
10.权利要求1-6之一的融合蛋白在制备用于预防或治疗FGF-23表达升高而导致的疾病（优选是矿物质代谢失衡或其引发的疾病，如低磷血症、慢性肾病和/或慢性心肌病）的药物中的应用。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020212626A1 (en) * | 2019-04-19 | 2020-10-22 | Genethon | Gene therapy of fibroblast growth factor 23 related hypophosphatemic diseases |
| CN112110988A (zh) * | 2020-08-21 | 2020-12-22 | 温州医科大学 | 一种具有毛发生长作用的多肽类似物及制备方法和应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103224557B (zh) * | 2012-08-08 | 2014-10-01 | 温州医学院 | 一种长效型成纤维细胞生长因子-23拮抗剂的开发 |
| WO2015149069A1 (en) * | 2014-03-28 | 2015-10-01 | New York University | Fgf23 fusion proteins |
-
2016
- 2016-08-24 CN CN201610720198.XA patent/CN106220741B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103224557B (zh) * | 2012-08-08 | 2014-10-01 | 温州医学院 | 一种长效型成纤维细胞生长因子-23拮抗剂的开发 |
| WO2015149069A1 (en) * | 2014-03-28 | 2015-10-01 | New York University | Fgf23 fusion proteins |
Non-Patent Citations (1)
| Title |
|---|
| 陈玉斌,等: "GST与FGF23 C末端71 个氨基酸融合蛋白的表达、纯化及其免疫原性", 《吉林大学学报(医学版)》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020212626A1 (en) * | 2019-04-19 | 2020-10-22 | Genethon | Gene therapy of fibroblast growth factor 23 related hypophosphatemic diseases |
| CN113692411A (zh) * | 2019-04-19 | 2021-11-23 | 吉尼松公司 | 成纤维细胞生长因子23相关的低磷酸盐血症的基因治疗 |
| CN112110988A (zh) * | 2020-08-21 | 2020-12-22 | 温州医科大学 | 一种具有毛发生长作用的多肽类似物及制备方法和应用 |
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